Visible Light-Driven Reductive Azaarylation of Coumarin-3-carboxylic Acids

In the manuscript, reductive and decarboxylative azaarylation of coumarin-3-carboxylic acids is described. It utilizes the photocatalytic activation of (cyano)azaarenes in the presence of fac-Ir(ppy)3 as a photocatalyst. The methodology is versatile and provides access to biologically relevant 4-substituted-chroman-2-ones. Visible light, photoredox catalyst, base, anhydrous solvent, and inert atmosphere constitute key parameters for the success of the described strategy. The developed methodology involves a wide range of coumarin-3-carboxylic acids as well as (cyano)azaarenes.


■ INTRODUCTION
Chroman-2-one, pyridine, and their derivatives constitute privileged structural motifs present in various natural products. 1 Representative examples of both groups of compounds are shown in Scheme 1. Although these compounds are abundant in nature, synthetic methods for their preparation are of importance. 2 In this context, it is worth noting that pyridine is the second most frequent nitrogencontaining heterocyclic scaffold that is present in 62 U.S. FDA approved drugs displaying a wide range of biological activities. 3 Thus, the pyridine skeleton often serves as a "privileged" scaffold in drug design and discovery. Moreover, it is also a versatile building block utilized for the synthesis of chiral ligands applied in asymmetric catalysis. 4 As a consequence, a lot of effort has been devoted toward the development of methods for the synthesis of pyridine derivatives. 5 Recently, radical-based pyridylation reactions have attracted much attention, providing a flexible approach to pyridine derivatives by the application of photocatalysis. These strategies benefit from good functional group tolerance, procedural simplicity, and mild reaction conditions. 6 The addition of free radicals to electron-deficient olefins is known as Giese reaction (Scheme 2). 7 Recent advancements in this field arise from the development of photo-mediated methods allowing for the free-radical formation under mild and nontoxic conditions. 8 A decarboxylative Michael reaction based on nucleophilic addition to carboxylic-acid-activated olefins followed by a decarboxylation reaction constitutes a powerful synthetic tool. 9 Recently, we described the first photocatalytic, doubly decarboxylative Giese reaction applicable to a wide range of carboxylic acids. 10 Coumarin-3-carboxylic acids 1 constitute useful acceptors in this reaction, opening access to biologically relevant chroman-2-ones 3. 11 Given the interesting properties of coumarin and pyridine derivatives, the task of development of synthetic routes leading to hybrid molecules bearing both structural motifs was undertaken. Notably, the synthesis of hybrid molecules containing more than one biologically active unit constitutes an important approach in modern drug design. 12 Herein, we present our studies on the development of decarboxylative reductive arylation of coumarin-3-carboxylic acids. (Cyano)azaarenes were applied as nucleophiles in the Giese-type transformation. This methodology benefits from mild reaction conditions and a broad scope of substrates.

■ RESULTS AND DISCUSSION
Initially, reactions between cyanopyridine 2a and coumarin derivatives 1 bearing either no or various activating groups in the 3-position were performed (Table 1, entries 1−4). Experiments were performed in acetonitrile in the presence of 4a as a photocatalyst and triethylamine as a base under irradiation with blue light and an inert atmosphere at room temperature. When simple coumarin 5a was used, no reaction was observed. Therefore, EWG-activated coumarin derivatives 1b−e were tested. Surprisingly, derivatives 5b−d displayed no reactivity under these conditions. To our delight, the incorporation of the carboxylic acid moiety into the structure of coumarin 1a resulted in the formation of the desired product 3aa, indicating the crucial role of the carboxylic-acid-group activation in the devised reactivity ( With the optimized reaction conditions in hand (Table 1, entry 23), the scope of the developed methodology was evaluated (Schemes 3 and 4). Initially, various coumarin-3carboxylic acids 1a−m were tested in the reaction (Scheme 3). Acids 1b−f bearing electron-donating groups on the aromatic ring provided products 3ab−af with very good yields. For the coumarin carboxylic acid 1a with a t-butyl substituent at the 6position of the aromatic ring, the yield was the highest despite  All reactions were performed in a 0.1 mmol scale using 1a or 5 (1.0 equiv) and 2a (2.0 equiv) in the presence of the corresponding photoredox catalyst 4 (10 mol %) and the corresponding base (2.5 equiv) in the solvent (1 mL) for 24 h at room temperature. b Reaction performed under irradiation with blue light. c Reaction performed under irradiation with green light. d Reaction performed using 2a (3 equiv). e Reaction performed for 48 h. f Reaction performed in DMSO (3 mL). g Reaction performed using Et 3 N (1 equiv). h Reaction performed in the dark. i Reaction performed at a 2 mmol scale. j Reaction performed in the presence of TEMPO (1 equiv). the presence of a bulky t-butyl substituent. In the course of further studies, it was found that substrates 1 bearing electronwithdrawing groups delivered products 3 in diminished yields. Short reoptimization studies indicated that modification of a previously developed procedure (involving dropwise addition of coumarin carboxylic acids 1g−m in dry DMSO (1 mL) over 2 h to the reaction mixture, see general procedure for details) enabled the improvement of the results. Dropwise addition of coumarin carboxylic acids 1g−m suppressed its decomposition over reaction time. Under these conditions, the reaction using coumarins 1g−k bearing fluorine, bromine, or chlorine atoms at various positions provided the corresponding products 3g−k in moderate to high yields. It is only in the case of coumarin 1k with a chlorine substituent in the 8-position of the aromatic ring that the yield of the reaction dropped to 34%. Similar results were observed for doubly substituted coumarin 1l. In this context, it is worth noting that coumarin 1l was not effective in the previous decarboxylative reactions performed by our group. 9d,10 What is also worth emphasizing is that the reaction with doubly substituted coumarin 1m with two methoxy substituents in the aromatic ring provided the desired product 3am with very good yield.
Subsequently, the scope of the methodology with regard to different (cyano)azaarenes 2a−c was evaluated (Scheme 4). It was demonstrated that the developed protocol worked well for 4-and 2-substituted pyridines 2a and 2b as well as pyrimidine-2-carbonitrile 3c to give target products 3aa−3ca with very good yields. Disappointingly, no product formation was observed when cyanopyridines 2d and 2e were employed under optimized reaction conditions.
The postulated mechanism of the developed methodology begins with the blue light-driven excitation of the photocatalyst 4b (Scheme 5). Then, the electron transfer from the triethylamine to the photocatalyst takes place. Fluorescence quenching and cyclic voltammetry experiments confirmed the lack of quenching in the case of acids 1a as well as cyanopyridine 2a (for details, see the Supporting Information). Subsequently, the reduced Ir-catalyst acts as a reductant of the (cyano)azaarene 2a to give 7. The newly formed radical 7 undergoes the decarboxylative Giese-type reaction with the acceptor 8 to give 9 that undergoes hydrogen atom transfer to give 10. Two separate processes transform 10 into 3aa: (1) rearomatization of the pyridine ring via dehydrocyanation and (2) decarboxylative protonation to afford 3aa as the final product.

■ CONCLUSIONS
In conclusion, we have developed a decarboxylative photocatalytic reductive arylation of coumarin-3-carboxylic acids 1 that represents a unique application of free-carboxylic-acid-activated olefins in radical transformations. The reactions between coumarin-3-carboxylic acids 1a−m and (cyano)azaarenes 2a−c were realized under photocatalytic activation in the presence of only 3 mol % of fac-Ir(ppy) 3 . The methodology proved versatile, leading to biologically relevant 4-substituted-chroman-2-ones 3aa−ca in good to high yields under mild reaction conditions. ■ EXPERIMENTAL SECTION General Information. NMR spectra were acquired on a Bruker Ultra Shield 700 instrument, running at 700 MHz for 1 H and 176 MHz for 13 C. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CDCl 3 : 7.26 ppm for 1 H NMR, 77.16 ppm for 13 C NMR). Mass spectra were recorded on a Bruker Maxis Impact spectrometer using electrospray (ES+) ionization (referenced to the mass of the charged species). Analytical thin layer chromatography (TLC) was performed using pre-coated aluminum-backed plates (Merck Kieselgel 60 F254) and visualized by ultraviolet irradiation. Unless otherwise noted, analytical-grade solvents and commercially available reagents were used without further purification. For flash chromatography (FC), silica gel (w/ Ca, ∼0.1%, 230−400 mesh), green LED (50 W, λ = 525 nm), and blue LED (50 W, λ = 456 nm) were purchased from commercial supplier Kessil LED Photoreactor Lightning. Fluorescence measurements were performed using a Varian Cary Eclipse spectrofluorometer equipped with a thermostatted cell holder. Coumarine-3-carboxylic acids 1b−k were synthesized according to the literature procedure. 13 Catalyst 4c was synthesized according to the literature procedure. 14 6-Methyl-2-oxo-2H-chromene-3-carboxylic Acid (1b). Compound 1b was synthesized according to the literature procedure 13 as a white solid in 75% yield (153.0 mg). Analytical data were in accordance with the literature.
Cyclic voltammetry, fluorescence quenching, photochemical reaction setup, and copies of 1 H and 13 C NMR spectra (PDF) fruitful discussions. This contribution has been completed while the first author (EK) was the Doctoral Candidate in the Interdisciplinary Doctoral School of Lodz University of Technology, Poland. E.K. thanks Lodz University of Technology for financial support within the "FU2N" programme, project number: W3/11D/2022.